rs301289

Variant names:

• chr5-83310416-T-C
• rs301289
• NM_003401.5:c.894-42715T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003401.5(XRCC4):​c.894-42715T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 152,042 control chromosomes in the GnomAD database, including 35,823 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.65 (35823 hom., cov: 31)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 6 publications found

Genes affected

XRCC4 (HGNC:12831): (X-ray repair cross complementing 4) The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]

XRCC4 Gene-Disease associations (from GenCC):

• short stature, microcephaly, and endocrine dysfunction

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.894-42715T>C		intron_variant	Intron 7 of 7	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.894-42715T>C		intron_variant	Intron 7 of 7	5	NM_003401.5	ENSP00000379344.4

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98796 AN: 151924 Hom.: 35816 Cov.: 31

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.691

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.650 AC: 98835 AN: 152042 Hom.: 35823 Cov.: 31 AF XY: 0.644 AC XY: 47887 AN XY: 74332

African (AFR) AF: 0.341 AC: 14128 AN: 41434

American (AMR) AF: 0.654 AC: 9979 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2982 AN: 3472

East Asian (EAS) AF: 0.299 AC: 1544 AN: 5164

South Asian (SAS) AF: 0.722 AC: 3477 AN: 4818

European-Finnish (FIN) AF: 0.712 AC: 7528 AN: 10570

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56708 AN: 68002

Other (OTH) AF: 0.691 AC: 1456 AN: 2106

Alfa AF: 0.773 Hom.: 176624

Bravo AF: 0.627

Asia WGS AF: 0.569 AC: 1982 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.38
DANN	Benign	0.87
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs301289; hg19: chr5-82606235; COSMIC: COSV56534945;